Pharmaceutical compositions and a device for administering the same

ABSTRACT

A pharmaceutical tablet or lozenge is described, which comprises a non-absorbable pharmaceutically active agent, in combination with a tablet matrix, arranged for providing controlled and sustained release of said agent into the mouth and gastro-intestinal tract, from a buccal or sub-lingual location. Also disclosed, are buccal tablets formed from non-carigenic sugars and a device for holding a tablet or lozenge in a location within a patient&#39;s mouth, from which an active ingredient, from the tablet or lozenge, is releasable by the action of the patient&#39;s saliva.

DESCRIPTION

The present invention relates to improved pharmaceutical compositions.In particular, the present invention relates to pharmaceuticalcompositions in tablet form, formulated to provide a controlled andsustained release of a pharmaceutically active ingredient over anextended period of time. The invention also relates to pharmaceuticalcompositions in the form of buccal tablets or sub-lingual lozenges andto a device for retaining a sustained release or buccal tablet in placein a patient's mouth.

It has been recognised, for more than 10 years, that patients inintensive care units, particularly those who require artificalventilation, are extremely susceptible to bacterial infection. In manycases, despite good nursing care, patients die from bacterial infectionrather than from an original traumatic injury. Gram-negative bacteriaare responsible for most of these potentially pathogenic infections.Once a patient has been admitted to hospital, his endogenous aerobicflora are replaced by nosocomial (hospital originating) gram-negativebacteria, such as Pseudomonas, Acinetobacter and, Klebsiella, which mayrapidly colonise the oropharynx, stomach and. intenstines. Once thedigestive tract has been so colonised, subsequent colonisation andinfection of major organ systems may occur.

More than 80% of critically ill patients are colonised by nosocomialgram-negative bacteria within 10 days of admission to hospital (Northeyet al. (1974), Surgery, Gynaecology, and Obstetrics 139, 321-5: Sheild,Hammill and Neale (1979), Intensive Care Medicine 5, 171-81 and; Thorpe,Richards and Telfer (1979) Anaesthesia 34, 643-50) and these organismsare responsible for the majority of late infections (Rose & Babcok(1975) American Journal of Epidemiology 101, 495-501 and; Weinstein andKabins (1981) American Journal of Medicine 70, 449-54). Considerablesuccess has been achieved in reducing the incidence of such infection bythe prophylactic administration of non-absorbable antibiotics toselectively decontaminate the digestive tract. The antibiotics areselected to the potentially pathogenic aerobic gram-negativemicro-organisms from the digestive tract, leaving the mainly endogenousanaerobic flora substantially unaffected. This work was carried out byC. P. Stoutenbeek and H. K. F. Van Saene and co-workers since 1982 andhas been reported in: Journal of Antimicrobial Chemotherapy (1984) 14,supplement B, 203-211; Journal of Antimicrobial Chemotherapy (1987) 19 ,513-520 and; Intensive Care Medicine (1986) 12 , 419-423. Thenon-absorbable antibiotics were administered through a nasogastric tube,in the form of an extemporaneously prepared suspension of Polymyxin E(15%), Tobramycin (12%) and, amphotericin (73%), and applied to thebuccal mucosa in the form of a commercially available paste (ORABASERegistered Trade Mark, available from Squibb) containing 2% polymyxin E,2% tobramycin and 2% amphotericin B. Both preparations were administeredto patients every four hours, with gastric suction being applied for thefirst hour after administration. To prevent infections of therespiratory tract, systemic antibiotic prophylaxis may also be given tomultiple trauma patients.

Although prophylactic and selective decontamination of the digestivetract has proven to be very successful, it is difficult and timeconsuming in application. These difficulties have prevented the methodfrom becoming more widely used.

According to a first aspect of the present invention there is provided apharmaceutical tablet or lozenge, comprising a non-absorbablepharmaceutically active agent in combination with a tablet matrixarranged for providing controlled and sustained release of said agentinto the mouth and gastro-intestinal tract, from a buccal or sub-linguallocation. The term non-absorbable, when used herein to describe apharmaceutically active agent, defines such an agent that is notabsorbed into the blood, or bodily fluids in any substantial quantityfrom a normal and untraumatised human digestive tract.

Preferably, the tablet matrix is formulated so as to be erodible onexposure to the fluid present within the mouth.

An advantage of a pharmaceutical tablet or lozenge in accordance withthe present invention is that when placed in a buccal or sub-linguallocation in a patient's mouth, the tablet provides a controlled andsustained dose of the pharmaceutically active agent to the entiredigestive tract, from the mouth to the large intestine. Since thepharmaceutically active agent is non-absorbable, any systemic sideeffects that the agent may have are avoided and the likelihood ofcreating resistance to the agent is reduced. When the tablet matrix ischosen to be erodible, no residue or empty shell remains in a patient'smouth after the active agent has ken discharged.

Buccal tablets, sub-lingual lozenges and conventional pharmaceuticaltablets are all formulated to include pharmaceutically activecomponents. The distinction between a buccal tablet and a conventionalpharmaceutical tablet arises from the manner in which a buccal tablet isused. In use, a buccal tablet is placed between the lip and the gum andallowed to dissolve, or otherwise release its pharmaceutically activecomponent. With all hitherto known buccal tablets, this active componentis then absorbed through buccal tissues of the mouth. A sub-linguallozenge is similar, however it is designed to be placed under the tongueto dissolve, or otherwise release its pharmaceutically active component,which, conventionally, is absorbed through the sub-lingual area of themouth.

Erodible pharmaceutical tablets formulated to provide a sustained andcontrolled release of a medicament from within the stomach are knownand, for example, may be formed by compressing a hydroxypropylmethylcellulose (available from the Dow Chemical Corporation under the TradeMark Methocel) in admixture with a pharmaceutically active ingredientand other pharmaceutical excipients. See "Formulating Sustained ReleasedPharmaceutical Products with Methocel" The Dow Chemical Co., 1982.However, in these tablets the active ingredient is of a type which actssystemically by oral administration into the gastro-intenstinal tract,followed by subsequent absorption into the blood.

Controlled release buccal tablets and sub-lingual lozenges may also beformed from hydroxypropylmethyl cellulose and a suitable medicament.However as suggested above, such tablets and lozenges, conventionally,contain medicaments which are absorbed through the buccal or sub-lingualtissues of the mouth.

Compositions for sustained and controlled release tablets, includingbuccal tablets and sub-lingual lonzenges, are described in BritishPatent No. 1583801 and Published British Patent Application Nos.2061950; 2111386 and 2117239 and European Patent Application No.0157695, all in the name of Forest Laboratories Incorporated of 150 East58th Street, New York, N.Y. United States of America.

In a preferred embodiment of the first aspect of the present invention,the tablet matrix includes a water soluble cellulose derivative, whichmay be a hydroxypropylmethyl cellulose or a mixture ofhydroxypropylmethyl celluloses. In a preferred embodiment, the tabletmatrix includes an ethyl cellulose and a salt of carboxymethylcellulose, preferably the sodium salt.

Hydroxypropylmethyl celluloses are commercially available in severaldifferent grades. These include METHOCEL E,F,J, and K manufactured bythe Dow Chemical Co in the United States, HPM, manufactured by BritishCelanese, Limited and METALOSE SH manufactured by Shin-Etsu KK in Japan.The various grades available under each of the aforementioned TradeMarks represent differences in methoxy and hydroxypropyl content as wellas molecular weight. The designations of the various hydroxypropylmethylcelluloses are based on the viscosities of 1% aqueous solutions at 20°C. The viscosities range form 15 cps to 30,000 cps.

The rate at which an active ingredient is released from a tablet inaccordance with the present invention held in a buccal, or sub-linguallocation and the total period over which such a tablet remains activemaybe determined by altering the total and relative amounts of differentgrades of hydroxypropylmethyl cellulose in the tablet matrix. Thus, forexample, a tablet may be formulated to release its entire dose in amatter of minutes, or to release its dose at an even rate over a periodof several hours. Up to eight hours being possible.

In a preferred embodiment, the non-absorbable pharmaceutically activeagent is a non-absorbable antibiotic agent, or a mixture of such agents.Preferably, said antibiotic agent or agents is or are selected to have anarrow spectrum of activity and to be active only against selectedpotentially pathogenic organisms. A tablet or lozenge in accordance withthese preferred embodiments may be administered to a patient, in abuccal or sub-lingual location, in order to provide the patient with asustained prophylactic dose of antibiotics and to selectivelydecontaminate the patient's digestive tract. Thus the complexities ofthe previously practiced method of prophylactic and selectivedecontamination of the digestive tract, including the use of anasogastric tub extemporaneously prepared antibiotic mixtures andgastric suction, may be replaced by the simple and regularadministration of a tablet in accordance with the present invention tothe buccal or sub-lingual area of the patient's mouth.

In a further embodiment of the present invention, the non-absorbableantibiotic agent is a non-absorbable aminoglycoside, a non-absorbablepolymyxin, a non-absorbable polyene, a non-absorbable substitutedimidazole derivative, or a mixture of such agents. Preferably, a tabletin accordance with the present invention includes at least two andpreferably three such antibiotic agents. More preferably the antibioticagents belong to different ones of the above classes.

The non-absorbable aminoglycoside may be a non-absorbable form oftobramycin, framycetin, neomycin, netilmicin, gentamicin, orstreptomycin. The non- absorbable polymyxin may be colistin sulphate, orsulphur methylated coilstin. The antifungal polyene may be nystatin oramphotericin B. The non-absorbable substituted imidazole derivativemaybe non-absorbable forms of ketoconazole, miconazole or, clotrimazole.

In a further embodiment, the tablet matrix comprises a salivationpromotion agent, an inert tablet filler and an inert tablet lubricant.Varying the amount and nature of the fillers and lubricants in a tabletor lozenge, provides a further method of adjusting the rate of releaseof an active ingredient and the period over which the ingredient isreleased.

In an alternative embodiment, the non-absorbable agent is selected fortreating the digestive tract of immuno compromised patients, such asthose with leukaemia or HIV infection or others who have undergonetransplant surgery. In a further alternative embodiment thenon-absorbable agent is benzylmetronidazole.

Two buccally administered pharmaceutical preparations are currentlyavailable in the United Kingdom. The first is sold under the Trade MarkSUSCARD BUCCAL by Pharmax Ltd. of Bourne Road, Bexley, Kent. andincludes lactose in its formulation, together with glyceryl trinitrateas the active ingredient. The second preparation is sold under the TradeMrk BUCCASTEM by Reckitt and Colman Ltd. of DansomLane, Hull, NorthHumberside, and contains sucrose in its formulation, together withprochloroperazine maleate as the active ingredient.

Since both lactose and sucrose are carigenic it is most likely, in viewof their site of administration, that repeated use of buccal tablets orsub-lingual lozenges containing these sugars will cause dental caries.The risk of causing dental caries would be particularly acute withsustained and controlled release buccal tablets or sub-lingual lozengesincluding sucrose or lactose, because these must reside in a patient'smouth for long periods of time.

According to a second aspect of the present invention there is provideda pharmaceutical tablet or lozenge for administration in a buccal orsub-lingual location, comprising a pharmaceutically active agent incombination with a non-carigenic sugar. Preferred non-carigenic sugarsinclude sorbitol, mannitol and, xylitol. Advantageously, prolonged useof a tablet in accordance with the present invention will not promotethe formation of dental caries in a patient's teeth.

Surprisingly, the administration of buccal or sub-lingual tablets thatinclude non-carigenic sugars does not cause the gastro-intestinaldisturbances, that normally are associated with the use of such sugars.This is believed to be because such disturbances result from animmediate administration of the sugar in gram quantities; whereas atypical buccal tablet includes about 100 mg of sugar and the sugar fromthe tablet is released more slowly than with a conventional tablet.

In a preferred embodiment of the second aspect of the invention, abuccal tablet or sub-lingual lozenge in accordance with the presentinvention comprises less than 200 mg of non-carigenic sugar andpreferably less than 100 mg of non-carigenic sugar.

In a further preferred embodiment of the second aspect of the invention,a buccal tablet or sub-lingual lozenge in accordance with the presentinvention includes a water soluble cellulose derivative, which may be ahydroxypropylmethyl cellulose or a mixture of hydroxypropylmethylcelluloses. In a preferred embodiment, the tablet includes an ethylcellulose and a salt of carboxymethyl cellulose, preferably the sodiumsalt.

Further embodiments of the second aspect of the present inventioninclude hydroxypropyl cellulose, tablet lubricants, such as magnesiumstearate, stearic acid, sodium fumarate and colloidial silicon dioxideplus other components, such as flavourings and artifical sweetners, suchas aspartame.

The pharmaceutically active ingredient in the composition in accordancewith the second aspect of the invention may be selected from a widerange of possibilites. It may be systemically absorbable through thebuccal mucosa or sub-lingual tissues of the mouth, or be non-absorbablefor administration to the entire digestive tract. Examples of activeingredients suitable for use in compositions in accordance with thesecond aspect of this invention include antacids, anti-inflamatorysubstances, coronary vasodilators, cerebral vasedilators, peripheralvasodilators, anti-infectives, psychoteoptics, anti-manics, stimulants,anti-histamines, laxatives, decongestants, vitamins, gastro-intestinalsedatives, anti-diarrheal preparations, anti-anginal drugs,antiarrythmics, anti-hypertensive drugs, vasconstrictors,anti-coagulants, anti-thrombotics, analgesics, anti-pyretics, hypnotics,sedatives, anti-emetics, anti-nausiants, anti-convulsants, neuromuscularagents, hyper- and hypoglycaemic agents, thyroid preparations,diuretics, anti-spasmodics, mineral and nutritional additives,anti-obessity drugs, anabolic agents, anti-asmatics, expectorants, coughsurpressants, antibiotics and other anti-microbial agents, topicalanalgesics and local anaesthetics and, polypeptides.

In a preferred embodiment of the first aspect of the present invention,the tablet or lozenge is formulated in accordance with the second aspectof the invention and the tablet matrix includes a non-carigenic sugar,such as sorbitol, mannitol or, xylitol. Advantageously, the prolongeduse of a tablet in accordance with this preferred embodiment of thefirst aspect of the present invention will not promote the formation ofdental caries in a patient's teeth. Furthermore, as set out above,administration of buccal or sub-lingual tablets that includenon-carigenic sugars does not cause the gastro-intestinal disturbances,normally associated with the use of such sugars. This is believed to bebecause such disturbances result from an immediate administration of thesugar in gram quantities; whereas a typical buccal tablet includes lessthan 100 milligrams of sugar and the sugar from the tablet is releasedslowly over a significant period of time.

A difficulty, which has been encountered during the past and inconnection with buccal tablets, is that such a tablet may becomedislodged from between a patient's lip and gum, before all of its activeingredient has been released. The risk of this eventuality is more acutewith patients in intensive care units, who are often partially ortotally unconscious.

Accordingly and in a third aspect, the present invention provides atablet retaining device comprising means engageable to a patient andmeans for accommodating and retaining a pharmaceutical tablet orlozenge, wherein the device is arranged to hold a tablet or lozenge in alocation with a patient's mouth, from which an active ingredient, fromthe tablet or lozenge, is releasable by the action of the patient'ssaliva or other fluid within the mouth.

Advantageously, a device in accordance with the third aspect of thepresent invention can be used to accommodate and retain a pharmaceuticaltablet, comprising a pharmaceutically active agent in combination with atable matrix arranged to provide controlled and sustained release ofsaid agent, on exposure to a fluid in a patient's mouth. Thepharmaceutically active agent can be non-absorbable and the device,therefore, used in a method of treating a patient's mouth andgastro-intestinal tract with such a non-absorbable agent. Preferably,the device is used to hold a tablet or lozenge in accordance with thefirst aspect of the present invention, for use in any of the treatmentsin which tablets or lozenges in accordance with the first aspect of theinvention may be used. The most preferred of these treatments is that ofproviding a patient with a sustained prophylactic dose of antibiotics,to selectively decontaminate the patient's digestive tract.

In a preferred embodiment, a device according to the third aspect of theinvention is arranged to hold a tablet in a buccal location between apatient's gum and lip. This preferred embodiment can be used inconjunction with a conventional buccal tablet, or in conjunction with abuccal tablet in accordance with the first or second aspects of thepresent invention.

An advantage of devices in accordance with the third aspect of thepresent invention is that, when one is used to hold a tablet in themouth of a partially or totally unconscious patient, there is no risk ofthat patient inadvertantly swallowing or choking upon the tablet.

In a most preferred embodiment, the means engagable to a patient arearranged to be engaged upon one, or a plurality of teeth. Also, thedevice may be configured to hold a plurality of appropriately locatedtablets.

According to a fourth aspect of the present invention there is provideda pharmaceutical tablet or lozenge in accordance with the first aspectof the invention for administration in a buccal or sub-lingual locationin a method comprising the prophylactic and selective decontamination ofthe human or animal digestive tract.

According to a fifth aspect of the present invention there is providedthe use of a composition comprising a non-absorbable pharmaceuticallyactive agent, in combination with a tablet matrix arranged to providecontrolled and sustained release of said agent into the mouth andgastro-intestinal tract, from a buccal or sub-lingual location, in themanufacture of a medicament for the prophylactic and selectivedecontamination of the human or animal digestive tract.

Preferred, non-limiting formulations for buccal tablets in accordancewith the present invention are given below. The quantities of eachconstituent are given in terms of milligrams thereof per tablet.Typically, each tablet will weigh in the order of 50-200mg. Formulations1 to 3 are in accordance with the first aspect of the invention whereasall of the formulations are in accordance with the second aspect of theinvention.

    ______________________________________                                        Ingredient             amount/tablet                                          ______________________________________                                        Formulation 1                                                                 Colistin sulphate      2-15    mg                                             Tobramycin sulphate    2-15    mg                                             Amphotericin B         5-40    mg                                             Hydroxypropylmethyl cellulose                                                                        5-150   mg                                             Citric acid            2-20    mg                                             Mannitol               0-100   mg                                             Magnesium stearate     2-10    mg                                             Colloidal silicon dioxide                                                                            2-10    mg                                             Formulation 2                                                                 Colistin sulphate      2-15    mg                                             Framycetin             5-20    mg                                             Nystatin               5-40    mg                                             Hydroxypropylmethyl cellulose                                                                        50-150  mg                                             Citric acid            2-20    mg                                             Mannitol               0-100   mg                                             Magnesium stearate     2-10    mg                                             Colloidal silicon dioxide                                                                            2-10    mg                                             Formulation 3                                                                 Colistin sulphate      2-15    mg                                             Netilmicin             2-15    mg                                             Clotrimazole           5-40    mg                                             Hydroxypropyl cellulose                                                                              50-150  mg                                             Citric acid            2-20    mg                                             Xylitol                0-100   mg                                             Stearic acid           2-10    mg                                             Colloidal silicon dioxide                                                                            2-10    mg                                             Formulation 4                                                                 Glyceryl trinitrate    1-15    mg                                             Hydroxypropylmethyl cellulose                                                                        5-150   mg                                             Citric acid            2-20    mg                                             Mannitol               0-100   mg                                             Magnesium stearate     2-10    mg                                             Colloidial silicon dioxide                                                                           2-10    mg                                             Formulation 5                                                                 Prochloroperazine maleate                                                                            2-15    mg                                             Hydroxypropylmethyl cellulose                                                                        50-150  mg                                             Citric acid            2-20    mg                                             Mannitol               0-100   mg                                             Magnesium stearate     2-10    mg                                             Colloidal silicon dioxide                                                                            2-10    mg                                             Formulation 6                                                                 Colistin sulphate      2-15    mg                                             Hydroxypropyl cellulose                                                                              50-150  mg                                             Citric acid            2-20    mg                                             Xylitol                0-100   mg                                             Stearic acid           2-10    mg                                             Colloidal silicon dioxide                                                                            2-10    mg                                             ______________________________________                                        EXAMPLE 1                                                                     One thousand 100 mg buccal tablets in accordance with                         formulation 1 were prepared from the following                                ingredients:-                                                                 Ingredient         amount/g                                                   ______________________________________                                        Colistin sulphate  5                                                          Tobramycin sulphate                                                                              4                                                          Amphotericin B     25                                                         Methocel K         40                                                         Citric acid        5                                                          Mannitol           10                                                         Magnesium stearate 5                                                          Colloidal silicon dioxide                                                                        6                                                          ______________________________________                                    

The colistin sulphate, tobramycin sulphate, amphotericin B and themethocel K were mixed together and the remaining ingredients were thenadded to the blend which, thereafter, was mixed for a total of 30minutes. The resulting mixture was then compressed in a conventionaltableting machine into 1,000 cylindrical tablets, each weighing 100 mg.The pressure applied by the punch of the tableting machine was 5 tonsper square inch.

EXAMPLE 2

One thousand 150 mg tablets in accordance with formulation 2 wereprepared from the following ingredients:

    ______________________________________                                        Ingredients        amount/g                                                   ______________________________________                                        Colistin sulphate  10                                                         Framycetin         12                                                         Nystatin           30                                                         Methocel K         50                                                         Citric acid         8                                                         Mannitol           24                                                         Magnesium stearate  8                                                         Colloidal silicon dioxide                                                                         8                                                         ______________________________________                                    

The colistin sulphate, framycetin, nystatin and methocel K were firstmixed together and the remaining ingredients were then added thereto.The resulting mixture was blended for a total of 30 minutes and thencompressed into 1,000 cylindrical tablets in a conventional tabletingmachine. The tableting machine puch compressed each tablet at a pressureof 2 tons per square inch.

EXAMPLE 3

One thousand 200 mg tablets in accordance with formulation 3 wereprepared from the following ingredients:

    ______________________________________                                        Ingredients        amount/g                                                   ______________________________________                                        Colistin sulphate  5                                                          Netilmicin         10                                                         Clotrimzole        20                                                         Methocel K         140                                                        Citric acid        8                                                          Xylitol            12                                                         Stearic acid       3                                                          Colloidal silicon dioxide                                                                        2                                                          ______________________________________                                    

The above ingredients were blended together for a total of 45 minutesand, thereafter, compressed into a 1,000 cylindrical tablets of 200 mgin a conventional tableting machine. The tableting machine punchsubjected each tablet to a pressure of 7 tons per square inch.

EXAMPLE 4

One thousand 100 mg buccal tablets in accordance with formulation 1 wereprepared from the following ingredients:

    ______________________________________                                        Ingredient         amount/g                                                   ______________________________________                                        Glyceryl trinitrate                                                                              5                                                          Methocel K         30                                                         Citric acid        9                                                          Mannitol           45                                                         Magnesium stearate 5                                                          Colloidal silicon dioxide                                                                        6                                                          ______________________________________                                    

The Glyceryl trinitrate (absorbed in mannitol), and the methocel K weremixed together and the remaining ingredients were then added to theblend which, thereafter, was mixed for a total of 30 minutes. Theresulting mixture was then compressed in a conventional tabletingmachine into 1,000 cylindrical tablets, each weighing 100 mg. Thepressure applied by the punch of the tableting machine was 5 tons persquare inch.

EXAMPLE 5

One thousand 150 mg tablets in accordance with formulation 2 wereprepared from the following ingredients:

    ______________________________________                                        Ingredients        amount/g                                                   ______________________________________                                        Prochloroperazine maleate                                                                        10                                                         Methocel K         70                                                         Citric acid        15                                                         Mannitol           39                                                         Magnesium stearate  8                                                         Colloidal silicon dioxide                                                                         8                                                         ______________________________________                                    

The prochloroperazine maleate and the methocel K were first mixedtogether and the remaining ingredients were then added thereto. Theresulting mixture was blended for a total of 30 minutes and thencompressed into 1,000 cylindrical tablets in a conventional tabletingmachine. The tableting machine puch compressed each tablet at a pressureof 5 tons per square inch.

EXAMPLE 6

One thousand 200 mg tablets in accordance with formulation 3 wereprepared from the following ingredients:

    ______________________________________                                        Ingredients        amount/g                                                   ______________________________________                                        Colistin sulphate  5                                                          Methocel K         130                                                        Citric acid        8                                                          Xylitol            42                                                         Stearic acid       8                                                          Colloidal silicon dioxide                                                                        7                                                          ______________________________________                                    

The above ingredients were blended together for a total of 45 minutesand, thereafter, compressed into a 1,000 cylindrical tablets of 200 mgin a conventional tableting machine. The tableting machine punchsubjected each tablet to a pressure of 5 tons per square inch.

the above examples, example 1 to 3 are in accordance with the firstaspect of the invention, whereas all of the examples are in accordancewith the second aspect of the invention.

A tablet retaining device, in accordance with the third aspect of thisinvention will now be described, by way of example only, with referenceto the following drawings:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front view of a first such device;

FIG. 2 is a rear view of the device shown in FIG. 1;

FIG. 3 is a section A-A' in FIG. 1;

FIG. 4 is a front view of a second device in accordance with the presentinvention;

FIG. 5 shows a patient's mouth with a device, as shown in FIG. 1,engaged therein; and

FIG. 6 is a view of the same patient's mouth as shown in FIG. 5, butwith the top lip raised so that the tablet retaining device is fullyvisible.

The tablet retaining device illustrated in FIG. 1 to 3 is formed from aresilient plastics resin material, such as polystyrene, polycarbonate,or an acrylic plastic resin such as polymethylmethacrylate. The tabletretaining device is integrally formed, preferably by moulding, andincludes an elongate leg member 1 which forms a part of and links firstand second channel section clip portions 2 and 3.

The elongate leg member 1 has a rectangular cross section, is ofsubstantially uniform thickness along its length and, defines first andsecond parallel outwardly facing surfaces 5 and 6. A first end portion 7of the elongate leg member 1, has a greater width than the remainderthereof. The first end portion 7 of the elongate member 1 provides afirst rectangular Jaw plate 4 for the first clip portion 2. The firstclip portion 2 further comprises a second rectangular Jaw plate 8,spaced apart from the first Jaw plate 4 and parallel thereto. A bridgingportion 9, extending from a first margin 10 of the second rectangularJaw plate 8 to meet the first surface 5 of the elongate leg member 1,where the first end portion 7 broadens out from the remainder thereof,completes the first clip portion 2.

Both the Jaw plates 4 and 8 are substantially square in outline, withfacing surfaces of substantially the same area.

The second clip portion 3 comprises a first Jaw plate 11, defined by asecond end portion 21 of elongate leg member 1, a second rectangular Jawplate 12, spaced apart from the first Jaw plate 11 and substantiallyparallel thereto, and a bridging portion 13. The bridging portion 13 isin the form of an extension to the elongate leg member 1, which curvesthrough approximately 180° , to extend into the second rectangular Jawplate 12 of the second clip portion 3.

The second Jaw plate 12 of the second clip portion 3 faces the secondsurface 6 of the elongate leg member 1; whereas the second Jaw plate 8of the first clip portion 12 faces the first surface 5 of the elongateleg member 1.

The second jaw plate 12 of the second clip portion 3 is of a greaterwidth than the first Jaw plate 11 of the second clip portion 3, theremainder of the elongate leg member 1 and the Jaw plates 4 and 8 of thefirst clip member 2.

The first and second jaw plates 4 and 8 of the first clip member 2, bothdefine an array of ciruclar cross-section holes 14. The holes 14 definedby the first Jaw plate 4 are in register with corresponding holes 14defined by the second Jaw plate 8.

A first ridge 15 is defined along the edge portion of the second Jawplate 12 of the second clip member 3, remote from the bridging portion13, and faces the second surface 6 of the elongate leg member 1. Asecond similar ridge 16 extends across the second surface 6 of theelongate member 1, facing the first ridge 15.

The same reference numerals as used above to identify parts of thedevice shown in FIGS. 1 to 3, are used to identify corresponding partsof the device shown in FIG. 4. The difference between the two devices isthat the Jaw plates 4 and 8 of the first clip portion 2, of the deviceshown in FIG. 4, are of considerably greater width than the remainder ofsaid device and the entire device shown in FIGS. 1 to 3.

The Jaw plates 4 and 8 of the first clip portion 2 in the device shownin FIGS. 1 to 3 are dimensioned and spaced apart, so as to accommodate atablet 20, in the manner shown in FIGS. 1 to 3. The spacing between theJaw plates 4 and 8 is chosen so that the tablet 20 is resilientlygripped therebetween. Likewise, the Jaw plates 4 and 8 of the first clipportion 2 in the device shown in FIG. 4, are dimensioned to accommodatetwo tablets 20 in a side-by-side relationship, as shown in FIG. 4.

To use the device illustrated in FIGS. 1 to 3, a tablet 20 is pushedbetween the Jaw plates 4 and 8 of the first clip portion 2, until it islocated as shown in FIGS. 1 to 3 and tightly gripped between the Jawplates 4 and 8. The loaded device is then inserted into a patient'smouth 23 and the second clip portion 3 is engaged on a tooth 24 (seeFIGS. 5 and 6). The tooth is resiliently gripped between the first andsecond Jaw plates 11 and 12 of the second clip portion 3, in such a waythat the device cannot be accidentally dislodged. The device isinstalled in the orientation shown in FIG. 6, that is with the firstclip portion 2, holding the tablet 20 immediately adjacent to the buccalmucosa 25 and between the latter and the patient's top lip 26 (when thetop lip is in the normal relaxed position).

Fluids such as saliva, within the mouth can gain access to the tablet 20both through the holes 14 and through the gap between the jaw plates 4and 8 of the first clip portion 2. The holes 14, in the first Jaw plate4, allow matter disolved from the tablet to pass directly into contactwith the buccal mucosa 25.

The illustrated devices can be used in conjunction with any form oftablet which it is desired to hold in the mouth while its activeingredient is leached therefrom. Thus, these devices may be employed tohold conventional buccal tablets, which include active ingredients to beabsorbed through the buccal mucosa, sustained release conventionalbuccal tablets, sustained release tablets containing non-absorbableactive ingredients, such as those in accordance with the first aspect ofthe present invention, and other sustained release tablets whose activeingredients may be absorbed throughout the digestive tract. Mostpreferably, the device is employed together with tablets in accordancewith the first or second aspects of the present invention, especiallythose formulated in accordance with the above formulations and examples.In this regard, a tablet produced in accordance with one of examples 1to 6 should be placed in a device as shown in FIGS. 1 to 3 and thedevice then should be installed in a patient's mouth as shown in FIGS. 5and 6. The device and tablet should be left in place until the tablethas completely dissolved and, if necessary, removed, reloaded with afresh tablet and reinstalled in the patient's mouth. The time taken fora given tablet to dissolve and release its phamaceutically activecomponent(s) is dependent upon the type and relative quantity of theMethocel (or the like) which is used, and can be determined by carryingout appropriate trials.

Most preferably, a device as shown in FIGS. 1 to 3 is loaded with atablet made in accordance with one of examples 1 to 3. Such a loadeddevice can then be installed in a patient's mouth as aforesaid, toselectively decontaminate his mouth and digestive tract.

As suggested above, the rate at which any given tablet dissolves andreleases antibiotic can be determined experimentally. Tablets used forselective decontamination treatment are selected to provide the doseJudged appropriate for a particualr patient, over an appropriate period.Both the daily dose and the period over which it should be provideddepend upon a particualr patients dispositon. Thus, for example, asuitable daily dose may be provided by a tablet which dissolvescompletely within one hour, or at the other extreme may be provided bythree, successively administered, tablets that each take eight hours todissolve.

If the patient's salivary flow is reduced, and during the routinemaintenance of oral hygiene, the tablet and device may be sprayed withoral cleansing fluid or an artificial salivary agent to facilitate thedissolution of the tablet.

I claim:
 1. A pharmaceutical tablet or lozenge, comprising at least twonon-absorbable antibiotic agents, in combination with a tablet matrixfor providing controlled and sustained release of said agents, whereinthe tablet or lozenge is arranged for providing controlled and sustainedrelease of a prophylactic dose of said antibiotic agents, into the mouthand gastrointestinal tract, from a buccal or sub-lingual location forselectively decontaminating a human or animal digestive tract.
 2. Apharmaceutical tablet or lozenge as claimed in claim 1, wherein thenon-absorbable antibiotic agents are selected from the group consistingof non-absorbable aminoglycosides, non-absorbable polymyxins,non-absorbable antifungal polyenes and non-absorbable substitutedimidazoles selected from non-absorbable forms consisting ofketoconazole, miconazole and clotrimazole.
 3. A pharmaceutical tablet orlozenge as claimed in claim 1, wherein the tablet matrix is formulatedso as to be erodible on exposure to fluid present within the mouth.
 4. Apharmaceutical tablet or lozenge as claimed in claim 3, wherein thetablet matrix includes a water soluble cellulose.
 5. A pharmaceuticaltablet or lozenge as claimed in claim 3, wherein the tablet matrixincludes an ethyl cellulose and a salt of carboxymethyl cellulose.
 6. Apharmaceutical tablet or lozenge as claimed in claim 5, wherein theantibiotic agents are selected to have a narrow spectrum of activity andto be active only against selected potentially pathogenic organisms. 7.A method of treating the human or animal body comprising administering atablet as claimed in claims 1, in a buccal location, between a patient'sgum and lip.
 8. A tablet or lozenge as claimed in claim 1 wherein thetablet is a buccal tablet.
 9. A pharmaceutical tablet or lozenge asclaimed in claim 4, wherein the water soluble cellulose derivativecomprises at least one hydroxypropylmethyl cellulose.
 10. Apharmaceutical tablet or lozenge as claimed in claim 5, wherein the saltof carboxymethyl cellulose is sodium carboxymethyl cellulose.
 11. Apharmaceutical tablet or lozenge as claimed in claim 2, containing threeof the antibiotic agents.
 12. A pharmaceutical tablet or lozenge asclaimed in claim 11, wherein each of the three antibiotic agents belongsto a different member of the group.
 13. A pharmaceutical tablet orlozenge as claimed in claim 2, wherein each of the at least twoantibiotic agents belongs to a different member of the group.
 14. Apharmaceutical tablet or lozenge as claimed in claim 1, wherein thetablet or lozenge comprises less than 100 mg of non-cariogenic sugar.15. A pharmaceutical tablet or lozenge as claimed in claim 4, whereinthe water soluble cellulose derivative is selected from the groupconsisting of hydroxypropylmethyl cellulose, a mixture ofhydroxypropylmethyl celluloses, an ethyl cellulose and a salt ofcarboxymethyl cellulose.
 16. A pharmaceutical tablet or lozenge asclaimed in claim 14, wherein the non-cariogenic sugar comprises at leastone member selected from the group consisting of sorbitol, mannitol andxylitol.
 17. A pharmaceutical tablet or lozenge as claimed in claim 2,wherein said tablet or lozenge includes three antibiotic agents.
 18. Apharmaceutical tablet or lozenge as claimed in claim 2, wherein thenon-absorbable aminoglycosides are selected from non-absorbable formsfrom the group consisting of tobramycin, framycetin, neomycin,netilmicin, gentamicin, and streptomycin; the non-absorbable polymyxinsare selected from the group consisting of colistin sulphate and sulphurmethylate colistin; and the antifungal polyenes are selected from thegroup consisting of nystatin and amphotericin B.
 19. A pharmaceuticaltablet or lozenge as claimed in claim 1, wherein the tablet matrixcomprises a salivation promotion agent, an inert tablet filler and aninert tablet lubricant.
 20. A pharmaceutical tablet or lozenge asclaimed in claim 1, wherein the antibiotic agents are selected fortreating the digestive tract of immuno-compromised patients withleukaemia or HIV infection, or others who have undergone transplantsurgery.
 21. A pharmaceutical tablet or lozenge as claimed in claim 1,wherein one of the antibiotic agents is benzyl-metronidazole.
 22. Apharmaceutical tablet or lozenge, comprising at least two non-absorbableantibiotic agents, in combination with a tablet matrix for providingcontrolled and sustained release of said agents, wherein the antibioticagents are selected from the group consisting of non-absorbableaminoglycosides, non-absorbable polymyxins, non-absorbable antifungalpolyenes and non-absorbable substituted imidazoles, selected fromnon-absorbable forms consisting of ketoconazole, miconazole andclotrimazole and the tablet or lozenge is arranged for providingcontrolled release of said antibiotic agents into the mouth andgastrointestinal tract, from a buccal or sub-lingual location.
 23. Amethod of selectively decontaminating a human or animal digestive tractcomprising administering a tablet as claimed in claim 22, in a buccallocation between a patient's gum and lip.
 24. A pharmaceutical tablet orlozenge as claimed in claim 22, for administration in a buccal orsub-lingual location in a method comprising the prophylactic andselective decontamination of the human or animal digestive tract.
 25. Apharmaceutical tablet or lozenge as claimed in claim 22, wherein thenon-absorbable aminoglycosides are selected from non-absorbable formsfrom the group consisting of tobramycin, framycetin, neomycin,netilmicin, gentamicin, and streptomycin; the non-absorbable polymyxinsare selected from the group consisting of colistin sulphate and sulphurmethylate colistin; and the antifungal polyenes are selected from thegroup consisting of nystatin and amphotericin B.
 26. A pharmaceuticaltablet or lozenge as claimed in claim 22, wherein the tablet matrixcomprises a salivation promotion agent, an inert tablet filler and aninert tablet lubricant.
 27. A pharmaceutical tablet or lozenge asclaimed in claim 24 arranged for administration in a tablet retainingdevice comprising means engageable to a patient and means foraccommodating and retaining a pharmaceutical tablet or lozenge, whereinthe device is arranged to hold a tablet or lozenge in a location withina patient's mouth from which an active ingredient, from the tablet orlozenge, is releasable by the action of the patient's saliva or otherfluid within the mouth.
 28. A pharmaceutical tablet or lozengecomprising a non-absorbable pharmaceutically active agent comprising atleast one member selected from the group consisting of anaminoglycoside, a polymyxin, a polyene, an imidazole andbenzylmetronidazole, in combination with a tablet matrix comprising atleast one member selected from the group consisting of a salivationpromotion agent, an inert tablet filler, and an inert tablet lubricantarranged for providing controlled and sustained release of said agentinto the mouth and gastro-intestinal tract, from a buccal or sub-linguallocation.
 29. A method of selectively decontaminating a human or animaldigestive tract comprising administering a tablet comprising anon-absorbable pharmaceutically active agent, in combination with atablet matrix arranged for providing controlled and sustained release ofsaid agent into the mouth from a buccal location between a patient's gumand lip wherein the non-absorbable pharmaceutically active agentcomprises at least one non-absorbable antibiotic agent wherein saidtablet is retained in a device comprising means engageable to a patientand means for accommodating and retaining a pharmaceutical tablet orlozenge, wherein the device is arranged to hold a tablet or lozenge in alocation within a patient's mouth from which an active ingredient, fromthe tablet or lozenge, is releasable by the action of the patient'ssaliva or other fluid within the mouth.
 30. A method of selectivelydecontaminating a human or animal digestive tract comprisingadministering a tablet comprising a non-absorbable pharmaceuticallyactive agent, in combination with a tablet matrix arranged for providingcontrolled and sustained release of said agent into the mouth from abuccal location between a patient's gum and lip wherein thenon-absorbable pharmaceutically active agent comprises at least onenon-absorbable antibiotic agent.
 31. A tablet or lozenge as claimed inclaim 22, wherein the tablet is a buccal tablet.